The Promise and Peril of Precision Medicine

Abstract

We illustrate the work necessary to reverse course after identification of a KCNQ1 variant interpreted erroneously as causing long QT syndrome (LQTS) and to identify the true cause of a case of sudden death in the young. Surrogate genetic testing of a decedent's living brother identified a rare KCNQ1-V133I variant, which prompted an implantable cardioverter defibrillator and subsequent diagnosis of LQTS in other family members. Subsequently, this presumed LQT1 family came to our institution for further clinical evaluation and research-based investigations, including KCNQ1-V133I variant-specific analysis of the decedent, heterologous expression studies of KCNQ1-V133I, and a whole-exome molecular autopsy along with genomic triangulation using his unaffected parents' DNA. After evaluating several V133I-positive family members, clinical doubt was cast on the veracity of the previously levied diagnosis of LQT1, resulting in a re-opening of the case and an intense pursuit of the lethal substrate. Furthermore, the decedent tested negative for V133I, and heterologous expression studies demonstrated a normal cellular phenotype for V133I-containing Kv7.1 channels. Instead, after whole-exome molecular autopsy, a de novo pathogenic variant (p.R454W) in DES-encoded desmin was identified. As detailed herein, the forensic evaluation of sudden death in the young requires meticulous focus on the decedent followed by a careful and deliberate assessment of the decedent's relatives. Surrogate genetic testing can have disastrous consequences and should be avoided. Genetic test results require careful scrutiny to avoid unintended and potentially devastating repercussions. Although the root cause of the decedent's tragic death would have remained a mystery, the unintended consequences for the living relatives described herein might have been avoided based on clinical grounds alone. All family members had electrocardiograms with normal QT intervals, making the diagnosis of familial LQTS unlikely. As such, if the clinicians caring for these patients had focused solely on clinical data from the survivors, there might have been no reason to embark on a path of inappropriate treatment based on genetic testing.

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team‐based Variant Classification

“…There are now multiple reports in the cancer and cardiology literature of the mis-classification of variants adversely affecting care, including the use of implantable cardioverter defibrillators and bilateral mastectomies that were in fact not medically indicated (Ackerman et al 2016;Arscott et al 2016;Kurian et al 2017;Manrai et al 2016;Maron et al 2009;Thompson et al 2014). Thus many of the factors that motivated our participants to take on variant classification are likely here to stay.…”

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

“…44 To reduce this risk, new guidelines for interpretation of DNA variants have been developed, including by the American College of Medical Genetics and Genomics. 22,45 Traditionally in hemophilia, only 1 affected member of a family has been genotyped.…”

Settling the score: variant prioritization and Mendelian disease

“…Wrong answers can be devastating to patient health and family planning. For example, in a recent example of incorrect variant interpretation, members of a family received a diagnosis of long QT syndrome and an inappropriate course of treatment 106 .…”